Process and intermediates for manufacture of 13-alkyl-3, 17-bisoxygenated gona-1, 3, (10)-trienes



Uni tcd States Patent 3,300,484 PROCESS AND INTERMEDIATES FOR MANUFAC- TURE 0F 13 ALKYL' 3,17 BISOXYGENATED GONA-1,3,5()-TRIENES Raphael Pappo, Skokie, 11]., assignor to G. D. Searle & C0., Chicago,.lll., a corporation of Delaware 'No Drawing. 7 FiledDec." 26, 1963-, Ser. No.7 333,657 h 18 Claims. (C l. 260-239.5) g

.The present invention is concerned with a novel process utilizing novel intermediates for the manufacture of 13- alkyl 3,17 bisoxygenated gona-1,3,5(10)-trienes which can be represented by the structural formula (lower alkyl) wherein R is hydrogen, a lower alkyl or tetrahydropyran- 2-yl group, Z is a carbonyl or hydroxymethylene radical, and the lower alkyl groups comprehended in that'representation are typified by methyl, ethyl, isopropyl, tertiarybutyl, pentyl, and hexyl, i.e,,

fewer than 7 carbon atoms.

The novel intermediates of the present invention are illustrated by the following structural formulas those radicals containing (lower alkyll moo and

(lower alkyl) wherein X can be a hydrazono, carbo-lower alkoxy)hydrazono, sernicarbazono, hydroxyimino, (lower alkylene)- dioxy, bis(lower alkoxy), ower alkylene)dithio, 0x0 or li O C-(lower alkyl) H 3,300,484 Patented Jan. 24, 1967 "ice vention are the 3-oxygenated l-vinyl-l-tetralols of the following formula wherein-1R has the identical meaning designated hereinbefore, and the 2-(lower alkyl)cyclopentane-1,3,4-triones represented by the structural formula (lower alkyDfiO When the latter triketones are allowed to react with one molecular equivalent of a' suitable carbonyl reagent, the 4-keto group can be selectively transformed'to produce the desired derivative. As a specific example, the reaction of Z-methylcyclopentane-1,3,4-trione with one mole of carbethoxyhydrazine in aqueous acetic acid affords the corresponding 4-carbethoxyhydrazone. v

The foregoing 1-[B-(3-substituted-1-alkyl-2,5-dioxocyclopentane ethylidene] 6-oxygenated-1,2,3 ,4-tetrahydronaphthalene intermediates are-obtained by reaction of the aforementioned starting materials as is shown below:

(lower. alkyl) By this process, for example, there is reacted 6-methoxyl-vinyl-l-tetralol with Z-methylcyclopentane-l,3,4-trione 4 carbethoxyhydrazone to afford 1-[fi-(3-carbethoxyhydrazono 1-methyl-2,5-dioxocyclopentano)ethylidene]-6- methoxy 1,2,3,4-tetrahydronaphthalene. Cyclodehydration of those substituted tetrahydronaphthalenes results in the gona-l,3,5(l0),8(9),l4-pentaene intermediates of the formula a (lower alkyl) V That process is catalyzed by acids or acidic dehydrating reagents. Specific examples of suitable reagents are hydrogen chloride, p-toluenesulfonic acid, formic acid, phosphoric acid, and phosphorous pentoxide. Typical of this process is the reaction of the aforementioned 1-[13-(3-carbethoxyhydrazono 1 methyl 2,5-dioxocyclopentano)- ethylidene]-6-methoxy-1,2,3,4-tetrahydronaphthalene with hydrochloric acid in methanol to yield 3-methoxyestra- 1,3,5(l0),8(9),14 pentaene-16,17-dione l6-carbethoxy- J hydrazone. Selective reduction of the latter gona-1,3,5 (l),8(9),14-pentaenes affords the corresponding'gona- 1,3,5(10),8(9)-tetraenes. That conversion is most conveniently accomplished by means of catalytic hydrogenation, suitable catalysts being palladium and platinum. The hydrogenation of 3-methoxyestra-1,3,5(10),8(9),l4 pcntaene-l6,17-dione 16-carbethoxyhydrazone, for example, in ethanol solution over 5% palladium-on-calcium carbonate catalyst produces 3-methoxyestra-1,3,5(l0),8 (9) -tetraene-l6,l7-dione lfi-carbethoxyhydrazone. Removal of the hydrazono, carbethoxyhydrazono, or semicarbazono function from the latter intermediates is conveniently accomplished by means of the Wolff- Kishner procedure. In that manner, 3-methoxyestra-1,3, 5 (l0),8 (9)-tetraene-l6,l7-dione 16carbethoxyhydrazone is converted to 3-rnethoxyestra-l,3,5(l0),8(9)-tetraen-17- one by refluxing in ethylene glycol with potassium hydroxide. As is described by H. Smith et al., Experentia, XIX, 394 (1963), the latter 3-oxygenated 13-alkylgona-L3, 5 l0),8(9)-tetraen-l7-ones can be reduced, typically with lithium in liquid ammonia, to yield the corresponding 3-oxygenated l3-alkylgona-1,3,5 ()-trien-l7-ols, which are oxidized, suitably with chromium trioxide, to produce the corresponding 17-ones. Those l7-ones and 17-ols .are estrogenic agents, the members wherein the 13-alkyl group is methyl being estrone and estradiol or their 3-ethers. The l7-ones are also intermediates to other useful pharmacological agents. Reaction with lithium acetylide, for

with an alkanedithiol such as 1,3-propanedithiol to produce the 17ii-hydroxy-16-one 1,3-propylenedithio ketal, and hydrogenolysis with Raney nickel of the thioketal function to produce the 175-01. An alternative method for that conversion involves reaction of the 16-hydroxyimino-17-ketone with zinc and acetic acid to afford the 16,17fi-ketol. By that series of reactions, 3-methoxyestra-l,3,5(10),8(9)tetraene-16,17-dione 16-oxime is converted to estra-1,3,5(10),8(9)-tetraene-3,l7;3-diol 3-methyl ether. When the protecting group at the 16-position is a ketal function, that moiety is removed by conversion to a thioketal and subsequent treatment as described above. The reaction of 17B-hydroxy-3-methoxyestra- 1,3,5(10),8(9)-tetraen-16-one ethylene ketal, for example, with 1,3-propanedithiol yields 17fi-hydroxy-3-rnethoxyestra-1,3,5(10),8(9)-tetraen-16-one 1,3-propylenedithioketal.

When the aforementioned 2-alkylcyclopentane-l,3,4- triones are reacted directly with the 3-oxygenated l-vinyll-tetralols described above, reaction occurs selectively at the 2-position to afford the l-[,8-(1-alkyl-2,3,5-trioxocyclopentano)ethylidene] 6-oxygenated l,2,3,4-tetrahydronaphthalenes of the formula (lower alkyl) 4 Cyclodehydration of those substances affords the corresponding 13-alkyl-3-oxygenated gona-1,3,5(l0),8(9),14- pentaene-l6,l7-diones. Reduction of the 17-ketone group with lithium tri-(tertiary butoxy) aluminum hydride followed by hydrogenation of the 14,l5-double bond over palladium-on-calcium carbonate catalyst results in the aforementioned 16,17B-ketols. Removal of the l6-keto group is accomplished by the procedure described hereinbefore.

The 16-(lower alkanoyl)oxy intermediates of this invention are obtained by the reaction of the aforementioned 6-oxygenated l-vinyl-l-tetralols with 4-(lower alkanoyl)oxy-2-alkylcyclopentane-1,3-diones. The latter diones are obtained by reduction of the Z-alkylcyclopentane-1,3,4-triones to the 4-hydroxy-l,3-diones, followed by acylation with a lower alkanoic acid in the presence of hydrogen chloride. In that manner, Z-methylcyclopentane-1,3,4-trione is catalytically hydrogenated with 10% palladium-on-carbon catalyst, and the resulting 4-hydroxy substance is allowed to react with acetic acid and hydrogen chloride, thus resulting in 4-acetoxy-2-methylcyclopentane- 1,3 -dione. 'Reaction of that dione with 6- methoxy-l-vinyl-l-tetralol, for example, in toluene in the presence of triethylamine affords 1-[fl-(2,5-dioxo-3-acetoxy-l-methylcyclopentano)ethylidene]-6-methoxy 1,2,3, 4-tetrahydronaphthalene. Cyclodehydration of that substance in methanol with aqueous hydrochloric acid affords 16 acetoxy 3 methoxyestra-1,3,5(10),8(9),14- pentaen-17-one, which is hydrogenated over 5% palladium-on-calcium carbonate catalyst to yield 16-acetoxy-3- methoxyestra-1,'3,5 10) ,8 (9)-tetraen-l7-one. Removal of the acetoxy group is eifectedby reaction with zinc in aqueous acetic acid, thus producing 3-methoxyestra-1,3, 5(l0),8(9)-tetraenl7-one.

As is described hereinbefore, the process and intermediates of the present invention are useful for the manufacture of 3,17-bis0xygenated gona-1,3,5(10)-trienes possessing pharmacological utility and also serving as intermediates to other potent pharmacological agents.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope to the details contained therein, as many modifications in materials and methods will be apparent from that disclosure to those skilled in the art. In these examples, temperatures are given in degrees 'centigrade C.) and quantities of materials in parts by weight unless otherwise noted.

Example 1 To a solution of 2.52 parts of Z-methylcyclopentane- 1,3,4-trione in 25 arts of methanol is added 10 parts of hydrazine, and the resulting mixture is allowed to stand at room temperature for about one hour. The solvent and excess hydrazine are removed by distillation at room temperature and reduced pressure to afford Z-methylcyclopentane-1,3,4-trione 4-hydrazone.

To a suspension of 14 parts of 2-methylcyclopentane- 1,3,4-trione 4-hydrazone in 22 parts of toluene is added 10.2 parts of triethylamine with vigorous stirring. After about 30 minutes at room temperature, a solution of 20.4 parts of 6-methoxy-l-vinyl-l-tetralol in 87 parts of toluene is added. The resulting reaction mixture is heated gradually to reflux temperature, and heating at that temperature together with continued stirringis maintained for about 3 hours, during which time the water of reaction is removed by means of a water separator. At the end of that refluxperiod the solvent is removed, by slow distillation over'a period of about 1 /2 hours, and the residual mixture is cooled, washed successively with 5% aqueous potassium hydroxide and water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure to yield 1-[/3-(2,5-dioxo-3-hydrazono-l-methyh 3. cyclopentano )ethylidene] 6-methoxy-1,2,3,4-tetrahydronaphthalene, represented by the structural formula EXAMPLE 2 To a solution of 2 52 parts of 2-methylcyclopentane-l,

3,4-trione in 25 parts of methanol containing parts of water is added 2.23 parts of semicarbazide hydrochloride and 3.35 parts of sodium acetate, and the resulting mixture is heated at the reflux temperature for about 5 minutes, then is cooled, and the crystals which form are collected by filtration, then dried to afford Z-methylcyclopentane-l,3,4-'trione 4-semicarbazone.

By substituting 18.3 parts of 2-methylcyclopentane-l, 3,4-trione 4-semicarbazone and otherwise proceeding according to'the process described in Example 1, l-[B-(Z,

is obtained.

EXAMPLE 3 To a solution of parts of 1-[/3-(2,5-dioxo-3-hydrazono 1 methylcyclopentano)ethylidene] 6 methoxyl,2,3,4-tetrahydronaphthalene in 120 parts of methanol is added, in a nitrogen atmosphere at room temperature, a solution of 12 parts of concentrated hydrochloric acid in parts of methanol. Stirring at room temperature is continued for about 1 /2 hours, after which time the reaction mixture is diluted with approximately 300 parts of water, then is neutralized by the addition of 10.2 parts of triethylamine. That aqueous mixture is extracted with benzene, and the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, then stripped of solvent at reduced pressure to yield 3-methoxyestra- 1,3,5(10),8(9),l4-pentaene-16,l7 dione l6-hydrazone. That substance can be represented by the structural formula yL3-semicarbazono)ethylidene] 6 methoxy --1,2,3,4-

tetrahydronaphthalene in the procedure described in Example 3 results in 3-methoxyestra-l,3,5(10),8(9),14-pen- 6 taene-16,l'Z-dione 16-semicarbazone of the structural formula' I EXAMPLE 5 To a solution of 6 parts of 3-methoxyestra-l,3,5(l0),

w8(9),ll-pentaene-16,17-dione 16-hydrazone in 200 parts of ethanolis added 0.6 part of 5% pall adium-on-calcium carbonate catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature until one molecular equivalent of hydrogen is absorbed. The catalyst is then removed by filtration, and the filtrate is evaporated to dryness at reduced pressure, resulting in 3-methoxyestra1,3,5(lO),8(9)-tetraene- 16,17-dione l6-hydrazone, which can b represented by the structural formula v ExAMPLE 6 When 6 parts of 3-methoxyestra-1,3,5(l0),8(9),14- pentaene-l6,l7-dione l6-semicarbazone is hydrogenated by the procedure described in Example 5, the resulting product is 3-methoxyestra-l,3,5(l0),8(9)-'tetraene-l6,l7- dione l6-semicarbazone whose structure is illustrated by the following formula 0 ll H -NNnoNrn orr3o EXAMPLE 7 To a solution of 3 parts of 3-methoxyestra-l,3,5(l0), 8,(9)-tetraene-l6,17-dione 16-hydrazone in 113 parts of ethylene glycol is added 0.6 part of potassium hydroxide, and the resulting reaction mixture is distilled slowly in a nitrogen atmosphere over a period of about 3 hours. The residual mixture is neutralized by the addition of one part of acetic acid, then is concentrated to a small volume at reduced pressure. Dilution of the residue with water affords a mixture which is extracted with benzene, and the benzene layer is separated, washed with water, dried over anhydrous sodium sulfate, then stripped of solvent in vacuo to afford 3-methoxyestra-1,3,5(10),8(9)- tetraen-17-one, represented by the structural formula C Hz a -(iii Example 8 The reduction of 3 parts of 3-methoxyestra-l,3,5(10), 8(9)-tetraene-16,17-dione IG-semicarbazone by the procedure described in Example 7 results in 3-meth'oxyestra-1,3,5(),8(9)-tetraen-17-one, identical with the product of Example 7.

Example 9 To a solution of 2 parts of 3-methoxyestra-l,3,5(10), 8(9)-tetraene-16,17-dione 16-hydrazone in 160 parts 'of methanol is added a solution of 0.5 part of sodium borohydride in 50 parts of water, and that reaction mixture is kept at room temperature for about 4 hours. Concentration of the mixture to approximately /3 the original volume at reduced pressure and room temperature affords a residue which is extracted with chloroform. The chloroform layer is separated, washed with water, dried over anhydrous sodium sulfate, then evaporated to dryness at reduced pressure to yield l7B-hydroxy-3-methoxyestra-l,3,5( 10) ,8 (9)-tetraen-16-one hydrazone, characterized by the following structural formula C II:

NNH:

Example 10 By substituting 2 parts of 3-methoxyestra-1,3,5(10), 8(9)-tetraen-l6,l7-dione 16-semicarbazone and otherwise proceeding according to the processes described in Example 9, 17fi-hydr0xy-3-methoxyestra-1,3,5(10),8(9)- tetraen-l6-one semicarbazone of the structural formula CHaO is obtained.

Example 11 The reaction of 3 parts of 17B-hydroxy-3-methoxyestra- 1,3,5(10),8(9)-tetraen-16-one hydrazone by the procedure described in Example 7 affords estra-1,3,5(10),8(9)- 3,4-trione tetraene-3,17fi-diol 3-methyl ether of the structural formula C Ila Example 12 By substituting 3 parts of 17B-hydroxy-3-methoxyestra- 1,3,5 (10),8(9)-tetraen-16-one semicarbazone and otherwise utilizing the procedure of Example 7, there is obtained estra-1,3,5(10),8(9)-tetraene-3,17fi-d'iol 3-methyl ether, identical with the product of Example 11.

Example 13 To a suspension of 1.25 parts of 2-methylcyclopentane- 1,3,4-trione in 15 parts of water containing 0.9 part of sodium acetate is added a solution of 0.7 part of hydroxy amine hydrochloride in 4 parts of water, and the resulting mixture is stirred until homogeneous. After standing at room temperature for about one hour, the mixture is filtered, and the resulting crystals are washed with water, then dried to afford 2-methylcyclopentane-1,3,4-trione 4-oxime, melting at about 220 with decomposition. Recrystallization from dioxane yields a pure sample melting at about 228230 with decomposition.

The reaction of 14.1 parts of Z-methylcyclopentane-l, 4-oxime with 6-methoxy-1-vinyl-l-tetnalol according to the procedure described in Example 1 results in 1-[B-(3-hydroxyimino-l-methyl-2,5-dioxocyclopentano)- ethylidene] 6-methoxy 1,2,3,4 tetrahydronaphthalene, represented by the structural formula Example 14 The cyclodehydration of 20 parts of l-[B-(B-hydroxyimino 1 methyl 2,5 dioxocyclopentano)ethylidene]- 6-methoxy-1,2,3,4-tetrahydronaphthalene by the processes described in Example 3 results in 3-methoxyestra-1,3, 5(10),8(9),14-pentaene-16,17-dione 16-oxime, which can be represented by the following structural formula 2 NO H.

Example 15 By substituting 6 parts of 3-methoxyestra-1,3,5(l0), 8(9),1 4-pentaene-16,17-dione 16-oXime and otherwise followmg the procedure described in Example 5, 3-mey 9 y thoxyestra-l,3,5( l) ,8 (9) tetraene-.l6,17-dione l' 6 -oxi r'ne of the structural formula i A mixture of 3.13 parts of 17B-hydroxy-3-methoxyestra-1,3,5( ),8(9)-tetraene-16-one oxime, 2.32 parts of levulinic acid, 0.2 part of p-toluenesulfonic acid monohydrate, and 100 parts of dioxane containing parts of water is allowed to stand at room temperature for about 48 hours, after which time the reaction mixture is neutralized by the addition of aqueous potassium bicarbonate. Concentration of the; mixture to a small volume by distillation at reduced pressure affords a residue which is extracted with chloroform. "The chloroform layer is separated, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and evaporated to dryness-in vacuo to afford V 1.7/3-hydroxye3r1nethoxyestra:1,3,;5 10 ,8 (9 tetraen-16-one, characterized by the structural formula followed by drying over anhydrous sodium sulfate affords a solution which is stripped of solvent at reduced pressure tojyield 1 7 3 hydroxy-3-methoxyestra-l,3,5(l0),8(9)- "tetraen-16-one 1,3-propylenethioketal.

That substance can be represented by the structural formula CHsO- I H .A mixture of Parts of. l l f y-3-methoxyestra- 0 ,8(9) tetraen.-16;one L37PPy q with. parts of W-,6 Raney nickel and 500,-parts of diy r oxane is heated at approximately for about 16 hours.

"sure and room temperature affords a residue. residue is added a solution of 3.2 parts of sodium hydroxide in ll) parts of methanol containing 10 parts of water, and the mixture is allowed to stand at room tem- The nickel catalyst is removed by filtration, and the filter cake is washedthoroughly with dioxane. Removal of the solvent by distillation of'the filtrate at reduced pressure afio'rds estra-l,3,5(10),8(9)-tetraene-3,l7B-diol 3- rnethyl ether, identical with the product of Example 11.

vljlbcample 19 To a solution of 16.8 parts of 1,3-propanedithiol in parts of acetic acid containing one part of anhydrous hydrogen chloride is added 5 parts of 2-methylcyclopenta'rie-1,3,4-trion'e; and the resulting reaction mixture is allowed'to-stand 'at roomtemperature for about 16 hours. Rer'noval of the" solvent by distillation at reduced pres- To that per'atu re for about 'l6hours, then is acidified, at about by means of hydrochloric acid. The acidic mixture is extracted with chloroform, and the organic layer is Washed with water, dried over anhydrous sodium sulfate,

'and stripped of solvent to yield Z-methylcyclopentane-l,3,

4-trione 4'-( 1,3-propylenedithioketal The substitution of 21.6 parts of 2-methylcyclopentane- 1,3, 4-trione 4- (1,3 propylenedithioketal) in the procedure of Example -1 affords 1-{/3-[1-methyl-2,5-dioxo-3-(1,3- -'propylenedithio)cyclopentano1ethylidene} 6 methoxy- '1,2,3,4-tetrahydronaphthalene, characterized by the structural formula omo- Example 20 The cyclodehydration of 24 parts of l-{B-[l-methyl- 2,5 dioxo 3 (1,3-propylenedithio)cyclopentano]ethylidene} 6- rnethoxy-l,2,3,4-tetrahydronaphthalene by the processes describedin Example 3 results in 3-methoxyestra-l,3,5(10),8(9),14-pentaene-l6,l7-dione 16-(1,3-proylenedithioketal). That substance can be represented by the following structural formula l I I CH2 Example 21 The hydrogenation of 7 parts of 3-methoxyestra-1,3, 5(l0),8(9),14 pentaene-16,l7-dione 16-(1,3-propylenedithioketal) according to the procedure of Example 5 results in 3-methoxyestra-1,3,5 10),8 (9)-tetraene-l6,17- dione l6-(1,3-propylenedithioketal), represented by the structural formula onto Example 22 When 2.4 parts of 3-methoxyestra-1,3,5(10),8(9)-tetraene-16,17-dione l6-(1,3-propylenedithioketal) is reduced, using the procedure described in Example 9, there is obtained 17 8hydroxy-3-methoxyestra-1,3,5( l),8 (9)-tetraen-16-one 1,3-propylenedithioketal. That substance is identical with the product of Example 17.

Example 23 I A mixture consisting of one part of.2-methylcyclopentane-1,3,4-trione, 5.7 parts of ethylene glycol, 0.1 part of p-toluenesulfonic acid monohydrate, and 176 parts of henzene is distilled slowly over a period of about 3 hours, during which time approximately /2 of the solvent is removed. Removal of the remaining volatile materials by distillation at reduced pressure atfords a residue to which is added a solution of 0.64 part of sodium hydroxide in 2 parts of methanol containing 2 parts of water. The resulting mixture is kept at room temperature for about 16 hours, then is cooled to 0-5" and made acidic by the addition of hydrochloric acid. Extraction of the aqueous Example 24 A solution of 20 parts of l-[fi-(li-ethylenedioxy-lmethyl 2,5 dioxocyclopentano)ethylidene] 6'- methoxy-1,2,3,4-tetrahydronaphthalene in 160 parts of methanol containing 3 parts of anhydrous hydrogenchloride is kept at room temperature for about 1 /2 hours, then is cooled to 05 and neutralized by the addition of 11 parts of anhydrous sodium carbonate. The inorganic salts are removed by filtration, and the filtrate is stripped of solvent by distillation at reduced pressure and room temperature. The resulting residue is extracted with benzene, and the benzene layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to produce 3-methoxyestra- 1,3 ,5 10) ,8 (9 14-pentaene-16, 17-dione l6-ethyleneketal, whose structure is illustrated by the following representation Example 25 The hydrogenation of 6.6 parts of 3-methoxyestra-1, 3,5(10),8(9),14 pentaene 16,17 dione 16-ethyleneketal by the procedure described in Example 5 affords 3- methoxyestra 1,3,5(10),8(9) tetraene 16,17 dione CHaO l 2 16-ethylenelgetal, which can be represented by the following structural formula Example 26 7 When 2.2 parts of 3-methoxyestra-1,3,5(10),8(9)-tetraene-16,17-dione l6-ethyleneketal is reduced by the proceduredescribed in Example 9, there is obtained 17;?- hydroxy 3 l methoxyestra 1,3,5( 10),8(9) tetraene- 16-one ethyleneketal, represented 'by the structural formula lExamp'le27 :2,

. The reaction of 12.9 parts of .l7fi-hydroxy-3-methoxyestr'a 1,3,5 (10.) ,8(9). tetraene 16 -'on'e ethyleneketal with 5.6 parts of"1,3-propanedithiol by the procedure described in Example 19 atfords 17,8 hydroxy 3 methoxyestra 1,3,5(10),8(9) tetraene 16 one 1,3- propylenedithioketal, identical with the product of Example 22.

Example 28 The substitution of 19 parts of 1-vinyl-1,2,3,4-tetrahydronaphthalene 1,6 diol in the procedures of Examples 1, 2, 13, 19, or 23 results in 1-[/3-(2,5-dioxo-3- hydrazono 1 methylcyclopentano)ethylidene] 6 hydroxy 1,2,3,4 tetrahydronaphthalene, 1 [B (2,5- dioxo 1 methyl 3 semicarbazonocyclopentano)ethylidene] 6 hydroxy 1,2-,-3,4 tetrahydronaphthalene, 1. [,B (,3 hydroxyimino 1.-.methyl 2,5 dioxocyclopentano)'ethylidene] --6,- hydroxy 1,2,3,4 tetrahydronaphthalene, -1 {B 1 --methyl 2,5 dioxo 3 (1,3-

propylenedithio)cyclopentano]ethylidene} 6 a hydroxy- 1,2,3,4 tetrahydronaphthalene, and 1 [B (3 ethylenedioxy 1 methyl- 2,5 dioxocyclopentano)ethyl idene] 6 hydroxy 1,2,3,4 tetrahydronaphthalene, respectively.

7 Example 29 2 By substituting an equivalent quantity of 1-[l3-(2,5 -d ioxo 3 hydrazono 1 methylcyclopentano)ethylidene]- 6-hydroxy-1,2,3,4-tetrahydronaphthalene and otherwise proceeding according tothe processes described in Example 3, 3 hydroxyestra' 1,3,5(10),8(9),14 pentaene- 16,17-dione 16-hydrazone is obtained.

Example 30 The substitution of an equivalent quantity of l-[fl- (2,5 dioxo 1 methyl 3 semicarbazono)ethylidene]- 6 hydroxy 1,2,3,4 tetrahydronaphthalene in the processes described in Example 3 results in 3-hyd oxy estra 1,3,5(10),8(9),14 pentaene 16,17 dione 16- semicarbazone.

Example 31 By substituting an equivalent quantity of 1-[18-(3-hyv droxyirnino 1 methyl 2,5 dioxocyc1opentano)ethylidene] 6 hydroxy 1,2,3,4 tetrahydronaphthalene and otherwise'p'roceeding according to the processes de- 13 scribed in Example 3, 3 hydroxyestra 1,3,5(10),8(9), 14-pentaene-16,17-dione 16-oxime is obtained.

Example 32 Example 34 To a solution of 70 parts of 1-vinyl-1,2,3,4-tetrahydronaphthalene-1,6-diol in 500 parts of dry benzene is added 40 parts of dihydropyran and 0.5 part of p-toluenesulfonic acid monohydrate. The resulting reaction mixture is kept at room temperature for about one hour, then is washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer is separated, dried over anhydrous sodium sulfate and. concentrated to dryness to alfordl-vinyl-LZ, 3,4- tetrahydronaphthalene 1,6 diol 6 (2-- tetrahydropyranyl) ether.

The substitution of an equivalent quantity of the latter pyranylether in the procedure of Examples 1, 2, 13, 19,

or 23 results in 1 [e (2,5 dioxo 3 hydrazono- 1 methylcyclopentano)ethylidenef] 6 (tetrahydropyran 2 yloxy) l,2,3,4 .tetrahydronaphthalene, 1 [B (2,5 dioxo 1 methyl 3 --semicarbazoncyclopentano)ethylidene] 6 (tetrahydropyran 2 yloxy) 1,2,3,4 tetrahydronaphthalene, 1- [B (3 hydroxyimino 1 methyl 2,5 dioxocyclopentano)ethylidene] 6 (tetrahydropyran 2 yloxy) 1-,2,3,4- tetrahydr'onaphthalene, 1 {,8 [1 methyl 2,5 dioxo- 3 (1,3 propylenedithio)cyc1opentano]ethylidene} 6- (tetrahydropyran 2 yloxy) 1,2,3,4 -"tetrahydronaphthalene, and 1 [,8 (3 ethylenedioxy 1 methyl- 2,5 dioxocyclopentano)ethylidene] 6 (tetrahydropyran 2 yloxy) 1,2,3,4 tetrahydronaphthalene, respectively.

' Example 35 By substituting an equivalent quantity of 1-[5-(25- dioxo-3-hydrazono-l-methylcyclopentano)ethylidene] 6- (tetrahydropyran 2 yloxy) 1,2,3,4 tetrahydronaphthalene, 1 [fi (2,5 dioxo 1 -'methyl 3 semicarbazonocyclopentano ethylidene] 6- tetrahydropyran-Z- yloxy)-1,2,3,4 tetrahydron aphthalene, 1 [fl (3 hydroxyimino 1 -.rnethyl 2,5 dioxocyclopentano)ethylidene] 6 (tetrahydropyran 2 yloxy) 1,2,3,4 tetrahydr-onaphthalene, 1 {p [1 7 methyl 2,5 dioxo 3- (l,3-propylenedithio)cyclopentano]ethylidene} 6 tetrahydropyran 2- yloxy) 1,2,3,4 tetrahydronaphthalene, or 1 9 (3 ethylenedioxy 1 methyl 2,5 dioxocyclopentano)ethylidene]-6-(tetrahydropyran 2 yloxy) .1,2,3,4 tetrahydronaphthalene, 3 (tetrahydropyran 2- yloxy)estra 1,3,5(10),8(9),14 pentaene 16,17 dione 16 hydrazone, 3 (tetrahydropyran 2-yloxy)estra-1,3,5 (10),8(9),14 pentaene 16,17 dione 16 semicarbazone, 3 (tetrahydropyran 2 7 yloxy)estra 1,3,5(l0), 8(9),l4 pentaene 16,1'7 dione 16 oxime, 3 (tetrahydropyran 2 yloxy)estra 1,3,5( l0),8(9),14 pentaene 16,17 dione 16 (1,3 ,propylenedithioketal), and 3- (tetrahydropyran 2 yloxy) estra 1,3,5(10),8(9),14 pentaene-16,17-dione 16-ethyleneketal, respectively, are obtained, 5 v

. Example 36 The substitution of an equivalent quantity of 3-hydroxyestra-1,3,5(l0),8(9),14 pentaene 16,17 dione 16-hydrazone, 3-hydroxyestra-1,3,5(10),8(9),14 pentaene-16, 17-dione 16-semicarbazone, 3 hydroxyestra 1,3,5(10), 8(9),14 pentaene 16,17 dione 16 oxime, 3 hydroxyestra 1,3,5(10),8(9),14 pentaene 16,17 dione 16 L (1,3 propylenedithioketal), or 3 hydroxyestra-l, 3,5(10),8(9),14 pentaene 16,17 dione 16 ethyleneketal in the procedure of Example 5 results in 3-hydrbxyestra 1,3,5(10),8(9) tetraene 16,17 dione 16 -hydrazone, 3 hydroxyestra 1,3,5(10),8(9) tetraene -'16, 17 dione 16-semicarbazone, "3-hydroxyestra-1,3,5(10),8(9)- tetraene 16,17-dione 16-oxime, 3-hydroXyestra-1,3,5(10), 8(9) tetraene 16,17 dione 16 (1,3 propylenedit-hioketal) and 3-hydroxyestra-1,3,5(10),8(9)-tetraene-16,17 dione 16-ethyle'neketal, respectively.

Example 37 By substituting an equivalent quantity of 3-(tetrahydropyran 2 yloxy)estra 1,3,5(1 0),8(9),14 pentaene l6, 17-dione 16-hydrazone, 3-(tetrahydropyran-2-yloxy)estra- 1,3,5(10),8(9),14 pentaene 16,17-dione 16-semicarbazone, 3 (tetrahydropyran-Z-yloxy)estra-1,3,5(10),8(9), 14-pentaene-16,17-dione 16-oxime, 3-(tetrahydropyran-2- yloxy)-estra-1,3,5(10),8 (9),14-pentaene-16,17-dione 16- (1,3 propylenedithioketal) or 3 (tetrahydropyran 2- yloxy)-estra-1,3,5(10),8(9),14-pentaene-16,17-dione t 16- ethyleneketal, 3 (tetrahydropyran 2 y1oxy)estra 1,3, 5(10),8(9) tet-raene 16,17 --dione 16 hydrazone, 3- (tetrahydropyran 2 y1oxy)estra 1,3,5(10),8(9), tetmeme- 16,17 dione 16 semicarbazone, 3 (tetrahydropyran 2 yloxy)estra 1,3,5(10),8(9) tetraene 16,17- dione 16 oxime, 3 (tetrahydropyran 2 yloxy)estr'a- 1,3,5(10),8(9)-, tetra'ene 16,17 dione 16 (1,3 propylenedithioketal), and 3 (tetrahydropyran 2 yloxy) estra 1,3,5(10),8(9) tetraene 16,17 dione 16 ethyleneketal, respectively, are obtained.

Example 38 The reaction of 43 parts of pentanone-Z with parts of ethyl oxalate according to the procedure described by Orchin and Butz, J. Amer. Chem. Soc., 65, 2296 (1943), affords et-hyl 4-ethyl-2,3,5 triketocyclophentylglyoxylate, which is allowed to react with phosphoric acid according to the procedure described in that publication to afford 2-ethylcyclopentane-1,3,4-trione.

Example 39 Bq substituting 2.8 parts of 2-ethy1cyclopentane-1,3,4- trione in the procedure of Examples 1, 2, 13, 19, or23, 2-ethylcyclopentane-1,3,4-trione 4-hydrazone, 2-ethylcyclopentane-1,3,4 trione 4-semicarbazone, 2-ethylcyclopentane 1,3,4 trione oxime, 2 ethylcyclopentane 1,3, 4-trione 4-(1,3-propylenedithioketal), and 2-ethylcyclopentane-1,3,4-trione 4-ethyleneketal, respectively, are obtained.

Example 40 {B-[1'-ethyl 2,S dioxo 3 (1,3 propylenedithio)cyclopentanoJethylidenel- 6 methoxy 1,2,3,4 tetrahydronaphthalene, and l-[fi-l-ethyl-3-ethylenedioxy-2,S-dioxocyclopentano)ethylidene] 6 methoxy 1,2,3,4 tetrahydronaphthalene, respectively, are obtained.

Example 41 The substitution of an equivalent quantity of l-[fl-(lethyl 3 hydrazono 2,5 dioxocyclopentano)ethylidene] 6 methoxy 1,2,3,4 tetrahydronaphthalene, 1 [6 (1 ethyl 2,5 dioxo 3 semicarbazonocyclopentano)ethylidene] 6 methoxy 1,2,3,4 tetrahydronaphthalene, 1 [fi (1 ethyl 3 hydroxyimino 2,5- dioxocyclopentano)ethylidene] 6 methoxy 1,2,3,4- tetrahydronaphthalene, 1 {/3 [1 ethyl 2,5 dioxo- 3 (1,3 propylenedithio)cyclopentano]ethylidene} 6- rnethoxy 1,2,3,4 tetrahydronaphthalene, or 1 [B (let-hyl 3 ethylenedioxy 2,5 dioxocyclopentano)ethylidene] 6 methoxy 1,2,3,4 tetrahydronaphthalene in the procedure of Example 3 results in l3-ethyl-3-meth0xygona 1,3,5(10),8(9),14 pentaene 16,17 dione l6- hydrazone, 13 ethyl 3 rnethoxygona-1,3,5(10),8,(9), 14 pentaene 16,17 dione semicarbazone, 13 ethyl- 3 methoxygona 1,3,5(10),8(9),14 pentaene 16,17- dione 16 oxime, 13 ethyl 3 methoxygona 1,3,5 '(10),8(9),l4 pentaene 16,17 dione 16 (1,3 propylenedithioketal) and 13-ethy1-3-met-hoxygona-1,3,5( l 8(9),l4-pentaene-16,17-dione 16 ethyleneketal, respectively.

Example 42 procedu're of Example 5, l3-ethyl-3-methoxygona-1,3,5

(),8(9), tetraene 16,17 dione 16 hydrazone, l3- ethyl 3 methoxyg-ona 1,3,5(10),8(9), tetraene 16, 17 dione 16 semicarbazone, 113 ethyl 3 methoxyestra-l,3,5(l0),8(9) tetraene 16,17 dione 16 oxime, 13 ethyl 3 methoxyestra 1,3,5(10),8(9)', tetraene- 16,17 dione 16 (1,3 propylenedithioketal') and 13- ethyl 3 me'thoxyestra 1,3,5(10),'8(9) tetraene 16, 1 17-dione 16-ethylene ketal, respectively, are obtained.

Example 43 By substituting an equivalent quantity of 13- ethyl-3- meth0xygona-1,3,5 10) ,8 (9) -tetraene-l6,17-dione 16-hydrazone or 13-ethyl-3-methoxygona-1,3,5(10),8(9)-tetraene-16,17dione 16-semicarbazone and otherwise proceeding according to the processes described in Example 7, 13 ethyl 3-methoxygona-1,3,5(10),8,(9)-tetraen-17-one of the structural formula is obtained.

- Example 44 The submission of an equivalent quantity of 13-ethy1- 3-methoxygona-1,3,5( 10) ,8 (9 -tetraene-'16, 17-dione 1. 6 oxime to the successive processes of Examples 16, 17, and -l 8 affords 1. -eIhy1gona-1,3,5 10 l ,8 (9') -tet1'aene-3,l7fi- 16 diol 3-methyl ether, characterized by the structural formula (3H3 or-r oir Example 45 The submission of an equivalent quantity of l3-ethyl- 3-methoxygona-l,3,5(10),8(9)-tetraene-16,17-dione 16- ethyleneketal to the successive processes described in Examples 26 and 27 affords 13-ethyl-17B-hydroxy-3- methoxygona-1,3,5(10),8(9)-tetraen-l6-one 1,3-propylenedithioketal.

Example 46 To a suspension of 1.25 parts of Z-methylcyclopentzine- 1,3,4-tri one inv parts of water containing 0.7 part of acetic acid is added, with stirring, one part by volume of carbethoxyhydrazine. The reaction mixture becomes homogeneous after standing for a few minutes, and the carbethoxyhydrazone begins to precipitate soon thereafter. After standing at room temperature for about minutes, the crystalline product is collected by filtration, washed with water, and dried to afford Z-methylcyclopentane-l,3, 4-trione 4-carbethoxyhydrazone, melting at about 205- 210 with decomposition. Recrystallization from diozane affords the pure material as prisms, melting at about 203204'with decomposition.

Example 47 Example 49 The catalytic hydrogenation of an equivalent quantity of 3 methoxyestra-1,3,5(10),8 (9),l4-pentaene-l6,17-dione l6-carbeth0xyhydrazone by the processes described in Example 5 affords 3-methoxyestra-1,3,5(10),8(9)-tetraene-16,17-dione 16-carbethoxyhydrazone.

Example 5 0 By substituting an equivalent quantity of 3-methoxyestra-1,3,5(10),8(9)-tetraene-16,17-dione 16-carbethoxyhydrazone and otherwise proceeding according to the processes described in Example 7, there is obtained 3- methoxyestra 1,3,5(l0),8(9)-tetraen-17-one, identical with the product of Example 7.

Example 51 To a solution of 1.5 parts of 2-methylcyclopentane-1,3,

- 4-trione in 168 parts of isopropyl alcohol containing parts of water isadded 0.2 part of 10% palladium-oncarbon catalyst, and the resulting hydrogenation mixture is stirred in a hydrogen atmosphere at room temperature until one molecular equivalent of hydrogen is absorbed. The catalyst is then removed by filtration, and the filtrate is concentrated to dryness at reduced pressure to afford 4-hydroxy-2-methylcyclopentane-1,3-dione.

The latter crude dione is dissolved in 25 parts of glacial acetic acid, previously saturated with hydrogen chloride, and the resulting solution is kept at room temperature for about 16 hours. Removal of the solvent by distillation at reduced pressure affords 4acetoxy-2- methylcyclopentane-l,3-dione.

Example 52 By substituting an equivalent quantity of 4-acetoxy-2- methylcyclopentane-l,3-dione and otherwise proceeding according to the processes described in Example 1, l-[,B- (2,5 dioxo-3-acetoxy-l-methylcyclopentano)ethylidene]- 6-methoxy-1,2,3,4tetrahydronaphtha1ene is obtained.

Example 53 The substitution of an equivalent quantity of l-[B- (2,5 dioxo-3 -acetoxy- 1 -methylcyclopentano ethylidene] 6-methoxy-1,2,3,4-tetrahydronaphthalene in the procedure of Example 3 affords 16-acetoxy-3-methoxyestra-1,3,5 (10),8(9),14-pentaen-17-one.

Example 54 By substituting an equivalent quantity of l6-acetoxy- 3 methoxyestra 1,3,5 (l),'8(9),14-pentaen-l7-one and otherwise proceeding according to the procedure of Example 16-acetoxy-3-rnethoxyestra-1,3 ,5 ('10) ,8 (9) tetraen-17-one is obtained.

Example 55 To a slurry of one part of 16-acetoxy-3-methoxyestra- 1,3,5(10),8(9)-tetraen-17-one in parts of water is added 5 parts of zinc and 10 parts of acetic acid, and the resulting reaction mixture is heated at the reflux temperature for about 3 hours. Filtration of the reaction mixture affords a solution which is extracted with chloroform, and the chloroform layer is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent at reduced pressure to afford 3-methoxyestra-1,3,5(10), 8(9)-tetraen-17-one, identical with the product of Example 7.

Example 56 The substitution of an equivalent quantity of 2methylcyclopentane-1,3,4-1trione in the procedure of Example 1 results in 1-[fi-(1-methyl-2,3,S-trioxocyclopentano)ethylidene] -6-methoxy- 1,2, 3 ,4-tetral1ydronapl1thaler1e.

Example 57 By substituting an equivalent quantity of 1-[ ,B-(l-methy1-2,3,5-1trioxocyo1opentano)ethylidene]-6 methoxy-1,2, 3,4-tetrahydronapht1halene and otherwise proceeding according to the process described in Example 3, 3-methoxyestra-l,3,5(l0),8(9),l4-pentaene-16,17 dione is obtained.

Example 58 To a solution of 2 parts of 3-methoxyestra-1,3,5(10), 8(9),14-pentaene-l6,l7-dione in 30 parts of tetrahydrofuran, cooled to 05, is added With stirring a cooled solution of 3 parts of lithium tri-(tertiarybutoxy) aluminum hydride in 30 parts of tetrahydrofuran. The reaction mixture is stirred for about minutes, then allowed to Warm gradually to room temperature and poured into a mixture of ice and water containing excess glacial acetic acid. The resulting aqueous mixture is washed with ether, then made alkaline by the addition of concentrated aqueous sodium carbonate, and extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, then stripped of solvent at reduced pressure to afford 17,8-hydroxy-3methoxyestra-1,3,5(10),8(9) ,14-pentaen-16-one.

18 Example 59 The hydrogenation of an equivalent quantity of 17/3- hydroxy-3 rnethoxyestra 1,3,5-(10),8(9),14-pentaenl6-one by the procedure described in Example 5 results in l7/3-hydroxy-3-methoxyestra 1,3,5(10),8(9) tetraen- 16-one, identical with the product of Example 16.

What is claimed is:

1. The process which comprises the steps of contacting a compound of the formula wherein R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl, with a compound of the formula 0 1 (lower alkyl):l X

wherein X is a member of the class of radicals consisting of hydrazono, carbethoxyhydrazono, semicarbazono, hydroxyimino, ethylenedioxy, propylenedithio, 0x0 and to afford a compound of the formula (lower alkyl) contacting the latter dione with an acidic cyclodehydrating reagent to yield a compound of the formula (lower alkyl) hydrogenating the latter gona-1,3,5(1U),8(9),14-pentaene to produce the corresponding gona-l,3,5(10),8(9)-tetraene of the formula (lower alkyl) and contacting the latter compound' with a reagent capable of removing the group represented by X to yield a compound of the formula (lower alkyl) 2. The process which comprises the steps of contacting a compound of the (formula wherein R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl with a compound of the formula (lower alkyDfi-X 0 wherein X is a member of the class of radicals consisting of hydrazono, semicanbazono, and carbethoxyhydrazono to afford a compound of the formula (lower alkyl) contacting the latter dione with an acidic cyclodehydrating reagent to yield a compound of the formula (lower alkyl) hydrogenating the latter gona-1,3,5(),8 (9),14-pentaene to produce the corresponding gona-1,3,5(10),8(9)-tetraene of the formula (lower allryl) and contacting the latter compound with potassium hydroxide to afford a compound of the formula a compound of the formula on I CH=CH wherein R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-2-y1, with a compound of the formula (lower alkybfix 0 wherein X is a member of the class of radicals consisting of hydrazono, carbethoxyhydrazono, and semicarbazono to afford a compound of the formula (lower alkyl) contacting the latter dione with an acidic cyclodehydrating reagent to yield a compound of the formula (lower alkyl) hydrogena-ting the latter gona-l,3,5(10),8(9),14-pentaene to produce the corresponding gona-1,3,5(10),8(9)-tetraene of the formula (lower alkyl) E contacting the latter l7-ket0ne with a reducing agent,

21 22 resulting in the corresponding l7p-hydroxy substance contacting the resulting gona-l,3,5(10),8(9)-tetraene of represented by the formula the formula (lower alkyl) (lower alkyl) OH 5 (I) X -NOH RO R0 and contacting the latter compound with potassium hywith a Feducing agent toafiord h P fidroxide to afford a compound of the f l contacting that 175-01 with an acidic reagent to yield the corresponding 16,17fl-ketol of the formula (lower alkyl) 0 H (lower alkyl) I OH 4. The process which comprises the steps of contacting acompoundof the formula contacting the latter ketol with 1,3-propanedithiol to afford the l-propylenedithio derivative, and contacting the latter substance with Raney nickel to yield a com- OH pound of the formula (lower alkyl) RO OH wherein R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl, with a compound of the formula (lower alkyl)' =NOH 5. The process which comprises the steps of contacting a compound of the formula O= 0H contacting the resulting compound of the formula |CH=C H,

(lower alkyl) "NOH wherein R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl, with a compound of the formula 0 RO l 0 (lower alkyl) with an acidic cyclodehydrating reagent, contacting the resulting gona-1,3,5,(10,8(9),14-pentaene of the formula (lower alkyl) r contacting the resulting compound of the formula 0 2K (lower alkyl) =NOH o with hydrogen in the presence of a hydrogenation catalyst,

23 24 g with an acidic cyclodehydrating reagent, contacting the gen, lower alkyl, and tetrahydropyran-Z-yl, with a comresulting gona-1,3,5(10),8(9),l4-pentaene of the formula pound of the formula (lower alkyl) 6 s q O (lower alkyl) contacting the resulting compound of the formula (lower alkyl) 0 R0 I S with hydrogen in the presence of a hydrogenation catalyst [02 s to yield the rgona-1,3,5(10),8 (9)-tetraene of the formula (lower alkyl) 0 B0 II 0 l with an acidic cyclodehydrating reagent, contacting the resulting gona-1,3,5(l0),8 (9),14-pentaene of the formula (lower alkyl) RO- s3 contacting the latter ketal with a reducing agent to afford the corresponding 17,8-01 of the formula (lower alkyl) OH R0 with hydrogen in the presence of a hydrogenation catalyst to yield the ,gona-1,3,5 (l0),8'(9)-tetraer1e of the formula (lower alkyl) o l s RO- contacting the latter substance with 1,3-propanedithiol to produce the corresponding thioketal of the formula (lower alkyl) R O OH I a o o contactmg the latter th1oketalwith a reducing agent to S alford the correspondmg 175-01 of the formula S (lower alkyl) i :s R0

and contacting that thioketal with Raney nickel to yield a compound of the formula R0 (lower alkyl) 0H and contacting that thioketal with Raney nickel to yield a compound of the formula (lower alkyl) OH 6. The process which comprises the steps of contacting a compound of the formula R0 B 7. The process of claim 2 wherein the group repre- OH=CH sented by R and lower alkyl is methyl.

8. The process of claim 2 wherein the group repre- RO sented by R and lower alkyl is methyl, and Z is a carbethoxyhydrazono group. 7 Y 9. The process of claim 3 wherein the group reprewherein R is selected from the group consisting of hydrosented by R and lower alkyl is methyl.

25 26 10. The process of claim 4 wherein the group repre- 16. A compound of the formula. sented by R and lower alkyl is methyl. CH! 11. The process of claim 5 wherein the group represented by R and lower alkyl is methyl. l

12. The process of claim 6 wherein the group represented by R and lower alkyl is methyl. O

13. A compound of the formula (lower alkyl) =X 0 wherein X is a member of the class of radicals consisting of hydrazono, carbethoxyhydrazono, semicarbazono, hy-

droxyimino, ethylenedioxy, propylenedithio, oxo and R O /O i l-(bwer alkyl) wherein X is a member of the class of radicals consisting of hydrazono, carbethoxyhydrazono, semicanbazono, hy- H droxylmmo, ethylenedloxy, propylenedlthlo, OX0 and and R is selected from the group consisting of hydrogen,

0 lower alkyl, and tetrahydropyran-2-yl. ognower alkyl) 17. A compound of the formula 0 r-r II and R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl.

14. A compound of the formula (lower alkyl) wherein X is a member of the class of radicals consisting of hydrazono, carbethoxyhydrazono, semicarbazono, hydroxyimino, ethylenedioxy, propylenedithio, 0x0 and I? RO O O-(hwer alkyl) wherein X is a member of the class of radicals consistin of hydrazono, carbethoxyhydrazono, semicarbazono, hy-

droxyimino, ethylenedioxy, propylenedithio, 0x0 and and R 13 Selected from the group conslstlng of y g lower alkyl, and tetrahydropyran-Z-yl. 18. A compound of the formula OC-(lower alkyl) 40 CH: 0

=X and R is selected from the group consisting of hydrogen, lower alkyl, and tetrahydropyran-Z-yl. 1s. A compound of the formula (lower alkyl) I 0 R0- ll 5 V X wherein X is a member of the class of radicals consisting of hydrazono, canbethoxyhydrazono, semicarbazono, hydroxyimino, ethylenedioxy, propylenedithio, 0x0 and wherein X is a member of the class of radicals COIlSlSlllls it of hyfim'zonot CaTbethPXYhYdIaZOHO sejm{carbazono and R is selected from the group consisting of hydrogen, droxyrmlno, ethylenedioxy, propylenedithio, 0x0 and lower alkyl, and tetrahydmpyran 2 y1 oguower alkyl) References Cited by the Examiner Windholz et al., Journal Org. Chem, Vol. 28, April 1963, pages 10921093 relied on.

H and R is selected from the group consisting of hydrogen, LEWIS GOTTS Pnmary Exammer' lower alkyl, and tetrahydropyran-Z-yl. ELBERT L. ROBERTS, Examiner, 

14. A COMPOUND OF THE FORMULA
 15. A COMPOUND OF THE FORMULA 